The present invention relates to certain compounds of formula (I), depicted below, having utility as hypoglycemic agents, methods for their use and pharmaceutical compositions containing them.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose or coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more sever cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
Schnur, U.S. Pat. No. 4,367,234 discloses hypoglycemic oxazolidinediones of the formula ##STR1## in which the phenyl ring is generally mono- or multisubstituted in the ortho/meta positions. Notably, with the exception of the 4-fluorophenyl analog, the parasubstituted derivatives are either inactive or possess a low level of hypoglycemic activity. Schnur, U.S. Pat. Nos. 4,332,952 and 4,342,771 further disclose a variety of similar oxazolidinedione hypoglycemic agents which are alternatively substituted at the 5-position with a heterocyclic group. These include certain furan, thiophene, pyrrole and pyridine derivatives.
Schnur, U.S. Pat. No. 4,617,312 discloses hypoglycemic thiazolidinediones of the formula ##STR2## where R.sup.c is lower alkyl, X.sup.a is F, Cl or Br, and Y.sup.a is hydrogen, chloro, lower alkyl or lower alkoxy. Notably, the compounds require ortho-substitution with an alkoxy group, and para-substitution is limited to hydrogen or halogen. Shoda et al. (Chem. Pharm. Bull., 30, 3563 (1982) describe the preparation of a series of 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-diones as antidiabetic agents.
Kawamatsu et al., U.S. Pat. No. 4,340,605, disclose hypoglycemic compounds of the formula ##STR3## wherein R.sup.e is a bond or lower alkylene and when R.sup.d is an optionally substituted five- or six-membered heterocyclic group including one or two hetero-atoms selected from N, O and S, L.sup.1 and L.sup.2 may each be defined as hydrogen. Based on the lack of hypoglycemic and plasma triglyceride lowering activity of certain non-ether analogs, it has been suggested that the boxed portion of the structural formula, including the ether oxygen, represents an essential feature for useful activity in this series of compounds; Sohda et al., Chem. Pharm. Bull. Japan, Vol. 30, pp. 3580-3600 (1982).
Sohda et al. also describe the compound of the formula ##STR4## as having weak hypoglycemic and plasma triglyceride lowering activity.
Eggler et al., U.S. Pat. No. 4,703,052, discloses hypoglycemic thiazolidinediones of the formula ##STR5## where the dotted line represents an optional bond, R.sup.f is H, methyl or ethyl, X.sup.b is O, S, SO, SO.sub.2, CH.sub.2, CO, CHOH or NR.sup.k, R.sup.k is H or an acyl group and the numerous definitions of R.sup.g, R.sup.h, R.sup.i and R.sup.j include R.sup.g, R.sup.h and R.sup.i as hydrogen or methyl and R.sup.j as optionally substituted phenyl, benzyl, phenethyl or styryl.
Meguro et al., U.S. Pat. No. 4,725,610 disclose a series of hypoglycemic thiazolidinediones of the formula ##STR6##
EP 283,035A and EP 299,620A describe benzoxazole and benzofuran linked thiazolidinediones as antidiabetic agents.